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. Author manuscript; available in PMC: 2016 Mar 9.
Published in final edited form as: Am J Med Genet A. 2015 Nov 17;170(3):559–564. doi: 10.1002/ajmg.a.37471

Paternal Uniparental Disomy 11p15.5 in the Pancreatic Nodule of an Infant With Costello Syndrome: Shared Mechanism for Hyperinsulinemic Hypoglycemia in Neonates With Costello and Beckwith–Wiedemann Syndrome and Somatic Loss of Heterozygosity in Costello Syndrome Driving Clonal Expansion

Karen W Gripp 1,*, Katherine M Robbins 2, Brandon S Sheffield 3, Anna F Lee 3, Millan S Patel 3, Stephen Yip 3, Daniel Doyle 4, Deborah Stabley 2, Katia Sol-Church 2
PMCID: PMC4784973  NIHMSID: NIHMS757008  PMID: 26572961

Abstract

Costello syndrome (CS) entails a cancer predisposition and is caused by activating HRAS mutations, typically arising de novo in the paternal germline. Hypoglycemia is common in CS neonates. A previously reported individual with the rare HRAS p.Gln22Lys had hyperinsulinemic hypoglycemia. Autopsy showed a discrete pancreatic nodule. The morphologic and immunohistochemistry findings, including loss of p57Kip2 protein, were identical to a focal lesion of congenital hyperinsulinism, however, no KCNJ11 or ABCC8 mutation was identified and germline derived DNA showed no alternation of the maternal or paternal 11p15 alleles. Here we report paternal uniparental disomy (pUPD) within the lesion, similar to the pUPD11p15.5 in Beckwith–Wiedemann syndrome (BWS). The similar extent of the pUPD suggests a similar mechanism driving hyperinsulinemia in both conditions. After coincidental somatic LOH and pUPD, the growth promoting effects of the paternally derived HRAS mutation, in combination with the increased function of the adjacent paternally expressed IGF2, may together result in clonal expansion. Although this somatic LOH within pancreatic tissue resulted in hyperinsulinism, similar LOH in mesenchymal cells may drive embryonal rhabdomyosarcoma (ERMS). Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis and pUPD11 occurred in all 8 ERMS samples from CS individuals. Somatic KRAS and HRAS mutations occur with comparable frequency in isolated malignancies. Yet, the malignancy risk in CS is notably higher than in Noonan syndrome with a KRAS mutation. It is conceivable that HRAS co-localization with IGF2 and the combined effect of pUPD 11p15.5 on both genes contributes to the oncogenic potential.

Keywords: Costello syndrome, neonatal hyperinsulinemic hypoglycemia, loss of heterozygosity, Beckwith–Wiedemann syndrome, 11p15.5, imprinting, HRAS mutation, p.Q22K

INTRODUCTION

Costello syndrome is a rare autosomal dominant disorder caused by activating mutations in the Harvey rat sarcoma viral oncogene homolog (HRAS) [Aoki et al., 2005; Gripp et al., 2006; Kerr et al., 2006], typically arising de novo in the paternal germline [Sol-Church et al., 2006; Giannoulatou et al., 2013]. It is one of several syndromic conditions resulting from mutations affecting the RAS/MAPK pathway, collectively referred to as rasopathies. Costello syndrome affects all organ systems, including skin and craniofacial features, structural cardiovascular anomalies and hypertrophic cardiomyopathy [Lin et al., 2011], developmental delay/intellectual disability, and an increased risk for solid tumors with embryonal rhabdomyosarcoma being the most common [Gripp et al., 2002; Kerr et al., 2006]. The growth pattern is characterized by relatively high birth weight, followed by failure-to-thrive and short stature, with relative macrocephaly driven by cerebral and cerebellar overgrowth [Gripp et al., 2010; Krencik et al., 2015]. Feeding difficulties are typically severe and necessitate gastrostomy tube placement. Growth hormone deficiency is common, and may contribute to hypoglycemia in older individuals. Hypoglycemia is common in neonates and young infants with Costello syndrome [Gripp and Lin, 2012], occurring in 44% compared to 9% in Noonan and 6% of cardio-facio-cutaneous syndrome patients, respectively [Myers et al., 2014]. Although the mechanism for the neonatal hypoglycemia remains largely unknown, it typically resolves in early infancy. This course resembles that of neonatal hypoglycemia in Beckwith–Wiedemann syndrome, known to be associated with hyperinsulinism [Arnoux et al., 2012]. Hyperinsulinemic hypoglycemia was documented by Alexander et al. [2005] in two neonates with Costello syndrome and additionally in one with the extremely rare HRAS p.Gln22Lys mutation [Sheffield et al., 2015]. The latter individual developed medically intractable pulmonary hypertension and hypertrophic cardiomyopathy and died. Sheffield et al. [2015] identified a pancreatic nodule appearing morphologically identical to a focal lesion of congenital hyperinsulinism, but were unable to specify the underlying molecular change within the nodule. Here we report on further studies aiming at identification of that underlying molecular mechanism, showing paternal uniparental disomy (UPD) within the lesion, similar to the UPD11p15.5 seen in individuals with Beckwith–Wiedemann syndrome.

MATERIALS AND METHODS

The proband was reported by Sheffield et al. [2015] for his rare de novo HRAS mutation and his clinical course including hyperinsulinemic hypoglycemia. His physical findings were typical for Costello syndrome (Fig. 1). He developed medically intractable pulmonary hypertension and hypertrophic cardiomyopathy and died at age 13 weeks,at an adjusted age of 5 weeks given his premature delivery. The patient's DNA was extracted from the pancreatic nodule and from splenic tissue as previously reported [Sheffield et al., 2015]. The parents enrolled in an IRB approved research protocol and provided cheek swab DNA samples for analysis.

FIG. 1.

FIG. 1

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Proband as neonate, note hydropic appearance, prominent philtrum, and lips. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

Mutation analysis was performed by PCR amplification of the HRAS exon 2 region using primers 5′-ACCTGTTCTGGAGGACGGTAA-3′ and 5′-CCTCTAGAGGAAGCAGGAGACA-3′. Sequencing was performed in both directions using the BigDye Terminator v3.1 Cycle Sequencing Kit (Thermo Fisher Scientific). Short tandem repeat analysis (STR) was performed using the AmpFLSTR Identifiler PCR amplification Kit (Thermo Fisher Scientific) as well as 18 STR loci located along chromosome 11, originally designed by Applied Biosystems for the Linkage Mapping Set (LMS) MD10. The AmpFLSTR Identifiler PCR amplification Kit amplifies TH01 although D11S4046 and D11S1338 are part of the LMS. All LMS loci were purchased as custom primer sets and are labeled with either 6-FAM or VIC as the reporter dye. Sequencing and STR loci were both analyzed on an ABI3130xl Genetic Analyzer.

Parental origin of HRAS mutations in individuals with Costello syndrome was assessed using polymorphic markers as described in Sol-Church et al. [2006].

RESULTS

Sanger sequencing of HRAS showed the previously identified c.64 C>A (p.Gln22Lys), present in heterozygous state in the splenic tissue derived DNA, but skewed with the mutant allele accounting for more than 50% of all reads in the pancreatic nodule (Fig. 2). Skewing occurred for markers D11S4046 and TH01 (Fig. 3). No deviation from the expected heterozygous state was seen at D11S1338 (Fig. 3). Comparison to STR analysis of parental samples revealed an over-representation of the paternal alleles with loss of maternal alleles at D11S4046 and TH01 (Figs. 3 and 4).

FIG. 2.

FIG. 2

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Sanger sequencing of HRAS showed the previously identified c.64 C>A (p.Gln22Lys), present in heterozygous state in the splenic tissue derived DNA, but skewed in the pancreatic nodule. Sequencing in both directions shows an increase of the mutant allele over the wild-type. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

FIG. 3.

FIG. 3

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Fragment analysis of chromosome 11 short tandem repeat (STR) markers shows heterozygous amplification in normal splenic tissue and allelic imbalance in the pancreatic nodule for markers D11S4046 and TH01. No deviation from the expected heterozygous state was seen at D11S1338. Parental results show the partial loss of heterozygosity in the nodule is due to paternal uniparental disomy. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

FIG. 4.

FIG. 4

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Genomic location of markers used to define the LOH in the pancreatic nodule. Skewing from a normal heterozygous state towards paternal UPD occurred in genomic DNA at three loci within 11p15.5: The mutation site within HRAS and STR loci D11S4046 and TH01. Loss of the protein p57KIP2, encoded by the maternally expressed CDKN1C, supports LOH into 11p15.4, but not past STR locus D11S1338 which was not skewed. All other STR loci centromeric to D11S1338 and on 11q were normal heterozygous. Positions are NC_000011.10. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

In keeping with the previously reported de novo origin of the HRAS mutation based on peripheral white blood cell derived DNA [Sheffield et al., 2015], the parental cheek swab derived DNA samples did not show the HRAS mutation (data not shown). Due to the absence of informative intragenic markers we cannot show directly that the HRAS mutation occurred on the paternal allele.

As part of our ongoing research on Costello syndrome, parental origin of apparent de novo HRAS mutations resulting in a phenotype consistent with Costello syndrome was informative for 78 individuals, in 74 paternal origin was documented. Two of the four maternally derived mutations were seen in siblings [Gripp et al., 2011], implying maternal gonadal mosaicism. Thus, at most, 2/78 (2.5%) were de novo mutations arising in the maternal germline.

DISCUSSION

The patient reported by Sheffield et al. [2015] had a rare de novo HRAS mutation and his clinical course included hyperinsulinemic hypoglycemia. He died at age 13 weeks, at an adjusted age of 5 weeks given his premature delivery. Upon autopsy, a discrete pancreatic nodule was identified. The morphologic and immunohistochemistry findings, including loss of p57Kip2 protein, were identical to a focal lesion of congenital hyperinsulinism [Sheffield et al., 2015], however, no mutation in KCNJ11 or ABCC8 was identified in DNA extracted from the nodule. Studies of germline derived DNA indicated no alterations to the maternal or paternal alleles at 11p15. Here we performed further molecular studies on the DNA derived from the nodule, revealing LOH of 11p15.5 but not extending beyond 11p15.4. The lack of p57Kip2 expression within the nodule strongly suggests that the maternal allele is lost, and this was confirmed through STR analysis (Fig. 3). We identified an overrepresentation of the mutated HRAS allele, above the expected 50%, in the DNA sample derived from the pancreatic lesion, but not in the splenic tissue (Fig. 2). In addition to skewing at the mutation site, allelic imbalance leading to partial loss of heterozygosity (LOH) was observed for additional markers in 11p15.5 (Fig. 3). This LOH was due to loss of the maternal alleles (Fig. 3). D11S1338 located at 11p15.4 (Fig. 4) as well as markers located on the q arm showed no allelic imbalance. These results demonstrate LOH for distal 11p within the pancreatic nodule, incomplete likely due to contamination by non-neoplastic cells. Due to the absence of discriminating SNPs within the HRAS alleles, we cannot show directly that the de novo mutation arose in the paternal germline. However, based on the high mutation rate for HRAS documented in the paternal germline [Giannoulatou et al., 2013] and the resulting overrepresentation of paternally derived HRAS mutations reported here, it is highly likely that this mutation arose in the paternal germline. Further, the allelic imbalance within the pancreatic lesion favors the paternal STR alleles (Fig. 3) as well as the mutant HRAS allele (Fig. 2), suggesting that the mutation occurred on the paternal chromosome 11. The related loss of thematernally derived distal 11p (Figs. 3 and 4) explains the observed lack of p57KIP2 protein within the pancreatic nodule [Sheffield et al., 2015], because CDKN1C encoding p57KIP2 is exclusively maternally expressed.

Hypoglycemia in Beckwith–Wiedemann Syndrome

Loss of heterozygosity at 11p15.5 with resulting paternal isodisomy and loss of the maternal allele accounts for 20% of Beckwith–Wiedemann syndrome cases, with other mechanisms affecting imprinted gene expression at 11p15.5 in the remainder [Shuman et al., 2000]. The abnormal expression of imprinted genes is associated with numerous physical abnormalities and understanding of each gene's respective contribution to the phenotype remains incomplete. About 50% of neonates with Beckwith–Wiedemann syndrome show hypoglycemia, typically due to hyperinsulinism [Hussain et al., 2005] resolving within the first weeks of life [Arnoux et al., 2012]. Of note, an individual with multiple congenital anomalies due to a paternally derived duplication 11p15.5p11.12 showed hyperinsulinemic hypoglycemia, consistent with the hypothesis that dosage skewing towards the paternal allele drives hyperinsulinemia [Gardeitchik et al., 2012].

Hypoglycemia in Costello Syndrome

Interestingly, compared to Beckwith–Wiedemann syndrome, hypoglycemia is almost as common in neonates and young infants with Costello syndrome, occurring in 44% compared to only 9% in Noonan and 6% of cardio-facio-cutaneous syndrome patients, respectively [Myers et al., 2014]. Although the underlying mechanism for neonatal hypoglycemia in Costello syndrome often remains unclear, hyperinsulinemia has occasionally been documented [Alexander et al., 2005]. In an individual with the rare HRAS p.Gly12Glu mutation, severe neonatal hypoglycemia due to congenital hyperinsulinism was associated with hypertrophy and hyperplasia of Langerhans islets seen on autopsy [Case 11 in Kerr et al., 2006]. Neonatal hypoglycemia in Costello syndrome is typically responsive to diazoxide treatment [Alexander et al., 2005] or resolves after a brief period of intervention and glucose level monitoring. This course is notably similar to that seen in Beckwith–Wiedemann syndrome, and differs from that of patients with focal hyperinsulinism.

Loss-Of-Heterozygosity at 11p in Hypoglycemia

Two distinct mechanisms involving LOH at 11p cause hyperinsulinemic hypoglycemia. Distal pUPD results in absence of p57KIP2, encoded by the exclusively maternally expressed CDKN1C, and is present in about 20% of individuals with Beckwith–Wiedemann syndrome, where the abnormal expression of imprinted genes in this region is the underlying cause for multiple physical differences including hyperinsulinism. Here we report pUPD of the same region (Fig. 4) in the pancreatic endocrine cell proliferation of an individual with Costello syndrome and hyperinsulinemic hypoglycemia.

The second mechanism affects LOH extending further centromerically and is seen in focal hyperinsulinism. Focal hyperinsulinism is caused by a paternally inherited ATP-sensitive potassium channel mutations in the biallelic expressed KCNJ11 or ABCC8, together with a somatic loss of maternal 11p15 [Suchi et al., 2012] and pUPD (Fig. 5). KCNJ11 and ABCC8 are located at 11p15.1, centromeric to HRAS and CDKN1C at 11p15.5 and 11p15.4, respectively. The paternally inherited KCNJ11 or ABCC8 mutation is present in all cells, whereas the secondary sporadic occurrence of LOH in pancreatic tissue accounts for the focal nature of the pancreatic lesion. The clinical course of focal hyperinsulinism is characterized by its unremitting nature and resistance to diazoxide treatment [Glaser, 2003], thus contrasting to the typical course of hypoglycemia in Beckwith–Wiedemann and Costello syndrome. No mutation in KCNJ11 or ABCC8 was found in the patient with Costello syndrome and hyperinsulinemia [Sheffield et al., 2015], and our results showed that the pUPD was limited to distal 11p (Figs. 3 and 4).

FIG. 5.

FIG. 5

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Diagram of UPD for chromosome 11 and of point mutations affecting either ABCC8 or HRAS, as seen in Beckwith–Wiedemann syndrome, focal familial hyperinsulinism or Costello syndrome, respectively. Somatic loss of heterozygosity in the respective tissue may result in clonal expansion. [Color figure can be seen in the online version of this article, available at http://wileyonlinelibrary.com/journal/ajmga].

Loss-Of-Heterozygosity in Costello Syndrome

Paternal UPD for distal 11p in the pancreatic nodule of the individual with Costello syndrome resulted from the somatic LOH in the pancreatic tissue (Fig. 5). Given the similar extent of the paternal UPD in some individuals with Beckwith–Wiedemann syndrome and their similar clinical course, it appears likely that the same mechanism drives the hyperinsulinemia. The paternally expressed IGF2, located just telomeric to the maternally expressed CDKN1C, may play a significant role. It exerts a growth promoting effect in embryonic and fetal development, mirroring the hypoglycemia most prominent in the neonatal and early infant ages. Although the reported somatic LOH within pancreatic tissue resulted in hypoglycemia, similar LOH may occur in mesenchymal cells giving rise to myoblasts (Fig. 5), allowing for development of embryonal rhabdomyosarcoma (ERMS), the most common malignancy in Costello syndrome. Indeed, paternal UPD11 occurred in all eight ERMS samples from Costello syndrome individuals [Robbins et al., 2015] and has been reported in nonsyndromic ERMS [Chen et al., 2015]. Uniparental disomy 11p was previously noted in Costello syndrome related ERMS [Kerr et al., 2003]. Kratz et al. [2007] found UPD at 11p15.5 in 5/6 nonsyndromic ERMS, and two samples harbored a heterozygous HRAS mutation. The heterozygosity of the HRAS mutations implied that they arose after the LOH and the authors concluded that “imbalance at 11p15.5 and HRAS mutations represent independent but cooperating events during ERMS development.” Parent-of-origin information was not available for these samples [Kratz et al., 2007] and the Costello syndrome ERMS studied by Kerr et al. [2003], but paternal UPD may be suspected based on information provided in this report and elsewhere [Chen et al., 2015; Robbins et al., 2015]. Interestingly, biallelic IGF2 expression has been linked to rhabdomyosarcoma tumorigenesis. It is possible that the growth promoting effects of the Costello syndrome causing HRAS mutation, which happens to be paternally derived in most cases, in combination with the increased signaling function of the paternally expressed IGF2 after coincidental somatic LOH, together result in the potential for clonal expansion. If the somatic LOH occurs in pancreatic tissue the focal lesion may cause hyperinsulinism, whereas such clonal expansion in mesenchymal cells may result in an ERMS. One may speculate that the same mechanism occurring in the precursor for the adrenal cells causes neuroblastoma, another tumor seen with increased frequency in Costello syndrome.

Allelic Imbalance in Hras and HRAS Related Tumors

In a HrasG12V knock-in mouse model of Costello syndrome developing skin papillomata, amplification of the mutant allele occurred only at the papilloma stage [Chen et al., 2009, 2014]. Angiosarcoma and forestomach papillomata showed similar increase in the copy number of the mutant allele [Chen et al., 2009], leading to the conclusion that further augmentation of the signal output from a single oncogenic Hras mutation is required for tumor development. HRAS allelic imbalance favoring the mutant allele was observed in human thyroid cancer cell lines, supporting this conclusion [Chen et al., 2014].

CONCLUSIONS

Discovery of LOH within the pancreatic lesion of an individual with Costello syndrome is important not only to understand commonly seen neonatal hypoglycemia in such patients, but additionally it highlights LOH with pUPD as a mechanism resulting in dysregulated cell growth and tumorigenesis. This mechanism is likely relevant not only to hyperinsulinism, but also for tumor and papillomata development in Costello syndrome. Somatic mutations in KRAS and HRAS occur with comparable frequencies in isolated malignancies. Yet, the risk for malignancies in Costello syndrome is notably higher compared to other rasopathies, including Noonan syndrome due to mutations in KRAS. Although this difference could be due to the differential effect and function of HRAS compared to KRAS, it is conceivable that the co-localization with IGF2 and the combined effect of paternal UPD for 11p15.5 on both genes contributes to the oncogenic potential.

ACKNOWLEDGMENTS

We thank the family for allowing us to learn from them. Research reported in this publication was supported in part by an Institutional Development Award (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under grant number P30GM114736 (COBRE) and grant P20GM103446 (DE-INBRE). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of NIGMS or NIH.

Footnotes

Conflict of interest: none

How to Cite this Article:

Gripp KW, Robbins KM, Sheffield BS, Lee AF, Patel MS, Yip S, Doyle D, Stabley D, Sol-Church K. 2015. Paternal uniparental disomy 11p15.5 in the pancreatic nodule of an infant with Costello syndrome: Shared mechanism for hyperinsulinemic hypoglycemia in neonates with Costello and Beckwith–Wiedemann syndrome and somatic loss of heterozygosity in Costello syndrome driving clonal expansion.

Am J Med Genet Part A 9999A:1–6.

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